Florfenicol (I) is a broad spectrum antibiotic having activity against Gram positive, Gram negative and thiamphenicol-resistant bacteria, as disclosed in U.S. Pat. No. 4,235,892. ##STR1##
Thiamphenicol (IX) and chloramphenicol (X) are structurally related antibiotics known in the art. ##STR2##
Several approaches to the synthesis of florfenicol have been reported, e.g. Tyson, Chem Ind., (1988)pp. 118-122; and U.S. Pat. No. 4,743,700. However, these processes typically suffer from low overall yields and require either a resolution step or expensive chiral starting materials.
Schumacher et al., J. Org. Chem., 18 (1990) pp. 5291-5294, describes a synthesis of florfenicol starling from a commercially available chiral starting material, e.g. compound (1). Compound (1) is converted to the oxazoline (2), to protect the secondary hydroxyl group, and (2) is converted to the fluoride (3). The oxazoline protecting group is removed by treatment with acid and the resulting amino-alcohol (4) converted to florfenicol I. However, the Schumacher et al. process again requires the use of expensive chiral starting materials. ##STR3##
Clark et al., in Synthesis, (1991) pp. 891-894, disclose a process for the synthesis of florfenicol via the stereoselective hydrolysis of ethyl D,L-threo-3-(4-methylthiophenyl)-serinate hydrochloride (5) using enzymes to give (2S,3R)-3-(4-methyl-thiophenyl)serine (7) and the unreacted ester ethyl (2R.3S)-3-(4-methyl-thiophenyl)serinate hydrochloride (6). The acid (7), and the ester (6), are then converted via alternative multi-step sequences to the R,R-oxazoline (2). Compound (2) is then converted to florfenicol by the process of Schumacher et al., described above. ##STR4##
The Clark et al. process, while avoiding the use of expensive chiral starting materials, is chemically inefficient, producing a mixture of chiral ester (6) and acid (7) which must be separately converted to (2). Thus, the prior art does not teach a chemically efficient stereoselective process for the synthesis of florfenicol that avoids the use of expensive chiral precursors.